Sekar Kathiresan (Verve)

Sekar Kathire­san show­cas­es his­toric mon­key da­ta in hunt for a once-and-done gene edit­ing ap­proach to pre­vent heart at­tacks

In a first for CRISPR — a field that’s seen quite a few his­toric moves in the past cou­ple of years — sci­en­tists have slashed cho­les­terol and lipid lev­els in mon­keys us­ing a tech­nique known as base edit­ing, gen­er­at­ing cru­cial proof-of-con­cept for both the biotech be­hind the ex­per­i­ment and a key part­ner.

Verve Ther­a­peu­tics de­signed two sim­i­lar ex­per­i­ments to test whether they can re­pro­duce pro­tec­tive mu­ta­tions in a pair of genes us­ing an ade­nine base ed­i­tor, which pre­cise­ly al­ters a cho­sen A to a G in the genome. CEO and co-founder Sekar Kathire­san pre­sent­ed the re­sults at a vir­tu­al keynote for the In­ter­na­tion­al So­ci­ety for Stem Cell Re­search over the week­end.

The base ed­i­tors ap­peared to have es­sen­tial­ly turned off genes, shut­ting down pro­duc­tion of cor­re­spond­ing pro­teins. That trans­lat­ed to a 60% drop in LDL with the PC­SK9 ther­a­py and a 64% plunge in triglyc­erides on the ANGPTL3 treat­ment.

When it comes to low­er­ing the col­lo­qui­al bad cho­les­terol, “60% is on par if not bet­ter than any oth­er treat­ment out there,” Kathire­san told End­points News just af­ter his pre­sen­ta­tion.

These re­sults are the cul­mi­na­tion of Kathis­er­an’s decades-long search for ge­net­ic clues for solv­ing coro­nary heart dis­ease, the lead­ing cause of death in the world. While di­rec­tor of the Cen­ter for Ge­nom­ic Med­i­cine at Mass­a­chu­setts Gen­er­al Hos­pi­tal and the Car­dio­vas­cu­lar Dis­ease Ini­tia­tive at the Broad In­sti­tute, he and col­leagues had iden­ti­fied eight genes that har­bor rare mu­ta­tions as­so­ci­at­ed with re­sis­tance to my­ocar­dial in­farc­tion. Af­ter show­ing in mice that they could ad­min­is­ter a one-time treat­ment for per­ma­nent low­er­ing of cho­les­terol, he left acad­e­mia to work on bring­ing it to hu­mans full-time.

There is, of course, still a long way to go. But Kathire­san be­lieves the new da­ta have lit up Verve’s path to the clin­ic.

They are still choos­ing be­tween the PC­SK9 and ANGPTL3 pro­grams as their lead can­di­date. Once they do — the dead­line will be the end of the year — an IND for pa­tients ge­net­i­cal­ly pre­dis­posed to high risk of heart at­tack is in sight for 2022.

Both pro­grams demon­strat­ed dra­mat­ic re­duc­tions in the tar­get pro­tein, cut­ting 89% of PC­SK9 and 95% of ANGPTL3 from the blood­stream. With the study lim­it­ed to two weeks, though, the dura­bil­i­ty ques­tions loomed large dur­ing the Q&A.

“We have en­cour­ag­ing da­ta out to sev­er­al months now,” Kathire­san said, ex­press­ing con­fi­dence that the edit­ing will be sta­ble long-term.

The rate of DNA reached 67% of the liv­er for PC­SK9 and 60% for ANGPTL3 which, Kathis­er­an point­ed out, rep­re­sents the ma­jor­i­ty of he­pa­to­cytes as around 30% of the liv­er is sup­port­ing tis­sue. Get­ting to not just ma­ture he­pa­to­cytes but al­so stem cells would be cru­cial. In pre­vi­ous re­search by oth­er groups, sci­en­tists have ob­served con­tin­ued edit­ing in mice cells even when they chop out parts of the liv­er and let it re­gen­er­ate.

Con­sid­er­ing the base ed­i­tors were de­ployed in vi­vo, safe­ty was al­so para­mount. Verve re­port­ed no off-tar­get ed­its in the 108 sites mea­sured — ow­ing, Kathire­san said, to the tech­nol­o­gy they have li­censed from Beam Ther­a­peu­tics.

Un­like the first gen­er­a­tion of CRISPR edit­ing, base edit­ing doesn’t snip at the site Cas9 brings it to; rather, through an en­zyme, it con­verts one base to an­oth­er chem­i­cal­ly.

“So it’s kind of in­ge­nious be­cause it us­es the GPS lo­cal­iza­tion fea­ture of Cas9, but it doesn’t use the dou­ble-strand break fea­ture of Cas9,” he said.

Apart from the mR­NA that forms the ed­i­tor, every Verve ther­a­py al­so con­sists of a guide RNA — picked out from hun­dreds — di­rect­ing the ma­chin­ery to the de­sired spot, all en­cap­su­lat­ed in a lipid nanopar­ti­cle en­gi­neered in col­lab­o­ra­tion with Van­cou­ver-based Acuitas.

De­liv­er­ing with lipid nanopar­ti­cles in­stead of a vi­ral vec­tor is a de­lib­er­ate choice.

“We need to get in, get the ed­i­tor and the guide RNA, get the edit­ing to hap­pen and then every­thing to go away as quick­ly as pos­si­ble,” Kathire­san said, “be­cause the longer the liv­er is ex­posed to the edit­ing ma­chin­ery, the more like­ly you are to get off-tar­get ef­fects. and lipid nanopar­ti­cles al­low de­liv­ery and then res­o­lu­tion of the process with­in a cou­ple of days.”

Al­so de­lib­er­ate is their de­ci­sion to part­ner wide­ly and as­sem­ble — not in­vent — all the tools that might aid their work. Base ed­i­tors aren’t go­ing to cov­er the full spec­trum of pos­si­ble and nec­es­sary changes as Kathire­san and his team go down their pri­or­i­tized list of eight genes. But they are tak­ing it one step at a time.

Biotech Half­time Re­port: Af­ter a bumpy year, is biotech ready to re­bound?

The biotech sector has come down firmly from the highs of February as negative sentiment takes hold. The sector had a major boost of optimism from the success of the COVID-19 vaccines, making investors keenly aware of the potential of biopharma R&D engines. But from early this year, clinical trial, regulatory and access setbacks have reminded investors of the sector’s inherent risks.

RBC Capital Markets recently surveyed investors to take the temperature of the market, a mix of specialists/generalists and long-only/ long-short investment strategies. Heading into the second half of the year, investors mostly see the sector as undervalued (49%), a large change from the first half of the year when only 20% rated it as undervalued. Around 41% of investors now believe that biotech will underperform the S&P500 in the second half of 2021. Despite that view, 54% plan to maintain their position in the market and 41% still plan to increase their holdings.

Covid-19 vac­cine boost­ers earn big thumbs up, but Mod­er­na draws ire over world sup­ply; What's next for Mer­ck’s Covid pill?; The C-suite view on biotech; and more

Welcome back to Endpoints Weekly, your review of the week’s top biopharma headlines. Want this in your inbox every Saturday morning? Current Endpoints readers can visit their reader profile to add Endpoints Weekly. New to Endpoints? Sign up here.

You may remember that at the beginning of this year, Endpoints News set a goal to go broader and deeper. We are still working towards that, and are excited to share that Beth Snyder Bulik will be joining us on Monday to cover all things pharma marketing. You can sign up for her weekly Endpoints MarketingRx newsletter in your reader profile.

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No­var­tis de­vel­op­ment chief John Tsai: 'We go deep in the new plat­form­s'

During our recent European Biopharma Summit, I talked with Novartis development chief John Tsai about his experiences over the 3-plus years he’s been at the pharma giant. You can read the transcript below or listen to the exchange in the link above.

John Carroll: I followed your career for quite some time. You’ve had more than 20 years in big pharma R&D and you’ve obviously seen quite a lot. I really was curious about what it was like for you three and a half years ago when you took over as R&D chief at Novartis. Obviously a big move, a lot of changes. You went to work for the former R&D chief of Novartis, Vas Narasimhan, who had his own track record there. So what was the biggest adjustment when you went into this position?

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Amit Etkin, Alto Neuroscience CEO (Alto via Vimeo)

A star Stan­ford pro­fes­sor leaves his lab for a start­up out to re­make psy­chi­a­try

About five years ago, Amit Etkin had a breakthrough.

The Stanford neurologist, a soft-spoken demi-prodigy who became a professor while still a resident, had been obsessed for a decade with how to better define psychiatric disorders. Drugs for depression or bipolar disorder didn’t work for many patients with the conditions, and he suspected the reason was how traditional diagnoses didn’t actually get at the heart of what was going on in a patient’s brain.

Susan Galbraith, Executive VP, Oncology R&D, AstraZeneca

As­traZeneca on­col­o­gy R&D chief Su­san Gal­braith: 'Y­ou're go­ing to need or­thog­o­nal com­bi­na­tion­s'


Earlier in the week we broadcast our 4th annual European Biopharma Summit with a great lineup of top execs. One of the one-on-one conversations I set up was with Susan Galbraith, the oncology research chief at AstraZeneca. In a wide-ranging discussion, Galbraith reviewed the cancer drug pipeline and key trends influencing development work at the pharma giant. You can watch the video, above, or stick with the script below. — JC

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Roche's Tecen­triq cross­es the fin­ish line first in ad­ju­vant lung can­cer, po­ten­tial­ly kick­ing off gold rush

While falling behind the biggest PD-(L)1 drugs in terms of sales, Roche has looked to carve out a space for its Tecentriq with a growing expertise in lung cancer. The drug will now take an early lead in the sought-after adjuvant setting — but competitors are on the way.

The FDA on Friday approved Tecentriq as an adjuvant therapy for patients with Stage II-IIIA non small cell lung cancer with PD-(L)1 scores greater than or equal to 1, making it the first drug of its kind approved in an early setting that covers around 40% of all NSCLC patients.

FDA ad­comm votes unan­i­mous­ly in sup­port of a J&J Covid-19 boost­er two months af­ter one-dose shot

The FDA’s Vaccines and Related Biological Products Advisory Committee (VRBPAC) on Friday voted 19-0 in favor of authorizing a second shot of J&J’s Covid-19 vaccine to follow at least two months after the initial dose.

Regulators don’t have to follow VRBPAC’s recommendation, but they almost always do. Considering that the CDC’s advisory committee has already been set to review the expanded EUA, VRBPAC’s recommendation is likely to be adopted.

Madhu Natarajan, Takeda rare disease development head

Drawn to the idea of turn­ing B cells in­to 'pro­tein fac­to­ries,' Take­da jumps in­to a mile­stone-heavy, $900M pact

Madhu Natarajan can trace his fascination with the idea of taking B cells and turning them into protein factories back 20 years, when he had his own lab at UT Southwestern. So when Natarajan, now the rare disease development head for Takeda, sat down for a meet-up with execs from Seattle-based Immusoft at the last in-person JP Morgan conference, they went straight into a brainstorming session.

“That B cells can take up residence and do what they do for a long time,” says Natarajan, pumping out proteins and “leveraging it into a therapeutic context,” hits his sweet spot for discovery deals. And he was deeply impressed by what he heard.

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Samarth Kulkarni, CRISPR CEO

CRISPR Ther­a­peu­tics claims safe­ty ad­van­tage in first big look at off-the-shelf CAR-T da­ta, but dura­bil­i­ty in ques­tion

CRISPR Therapeutics CEO Samarth Kulkarni thinks his company might have built the safest CAR-T therapy yet.

The gene editing biotech announced the first major batch of data from its off-the-shelf CAR-T program, showing that 58% of the 26 large B-cell lymphoma patients who received the therapy saw their tumors shrink and that 38% had no signs of cancer whatsoever.

Those response rates, outside experts say, are broadly in the range seen in trials for autologous CAR-T therapies such as Novartis’s Kymriah and Gilead’s Yescarta, bolstering the chance that off-the-shelf could eventually make the benefits of such therapies far more widely available. Uptake of the first-generation of CAR-Ts continues to be limited by the cost, time and infrastructure required to handle each person’s cells.

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